The Fitzsimons Lab

After a postdoctoral experience at the LACDR (currently Leiden Academic Centre for Drug Research), aimed to study the behavioral consequences for cognition of gene knockdown using RNA interference, I joined the Neuroscience Program of the Swammerdam Institute for Life Sciences, Faculty of Sciences, University of Amsterdam as Assistant professor in 2010. I became faculty member in 2013.

My lab is financed by the Innovational Research Incentive Scheme VIDI from The Netherlands Organisation for Scientific Research (NWO), the International Foundation for Alzheimer's Research (ISAO) and Alzheimer Nederland and by ERA-NET NEURON. The Network of European Funding for Neuroscience Research (NEURON) is a European Research Area Network (ERA-NET) co-funded by the European Commission that supports basic, clinical and translational research in the field of disease-related neuroscience. As a co-fund, this ERA-NET NEURON project receives local financial support from NWO/ZonMw, Hersenstichting Nederland, the National Initiative Brain and Cognition and is part of the Topsector Life Sciences & Health program. More information on our project can be found at http://reactnsc.com/

My lab studies the regulation of gene expression in neural stem cells. Within this frame, we focus on regulation by (ligand-activated) transcription factors, such as hormone receptors, and microRNAs. In particular, we study the effect that brain insults such as physical or psychological stress, epileptic seizures, traumatic brain injury and others may have on adult neural stem cells in the hippocampus and how they are associated with neurodegeneration and cognitive impairment.

News

Our recent article in Frontiers in Molecular Neuroscience is highlighted at the Scientific News page of the Faculty of Sciences, University of Amsterdam " A team of neuroscientists lead by Carlos Fitzsimons (SILS-UvA) have discovered how to revert effects of small RNA molecules present after a seizure, thereby protecting affected stem cells in the brain...The study by Fitzsimons and team supports the promise for a future application for RNA interference-based therapies for epilepsy syndromes"

The effect of convulsive seizures on adult hippocampal neural stem cells has been extensively studied. However, in many epilepsy patients, only non-convulsive seizures are observed. In our recent paper, we characterize for the first time the effect of non-convulsive seizures on adult hippocampal neural stem cells and demonstrate that simultaneous antagonism of two microRNAs rescues alterations in NSPC. Our observations support the possible use of anti-microRNA oligonucleotides (AMOs) for future seizure therapies.

The full-text article, Published in Frontiers in Molecular Neuroscience is available here (Open Acess):

Microglia are the immune cells of the brain and have recently been implicated in neurodegenerative diseases, such as Alzheimer's. Microglia dynamically adapt their morphology and function with increasing age. In a recent paper done in collaboration with my ex Ph.D. student Marijn Schouten, now at the AMC Amsterdam, we demonstrate that that age-associated elevations in glucocorticoid levels regulate microglia function and morphology. Our data show that glucocorticoids increase ramification of hippocampal microglia and may modulate age-associated changes in microglial morphology, demonstrating a new pathway by which glucocorticoids may promote age-associated brain disorders.

The full-text article, Published in Aging Cell is available here (Open Acess):

Scientific reproducibility is a growing concern and weak experimental practices may contribute to irreproducibility. To help tackling this problem, we have described an optimized and versatile protocol for stereotaxic intrahippocampal administration of Kainic Acid (KA) in mice with a C57Bl6 background. In this protocol, KA administration is combined with in vivo recording of neuronal activity with wired and wireless setups. The procedure was cross-validated in three independent research centers and consists of three main steps: Craniotomy, stereotaxic administration of KA, and placement of recording electrodes in intrahippocampal, and subdural locations. As such, the procedure can be easily adapted to the titrated intrahippocampal administration of other drugs. The Open Acess article describing the protocol can be found here:

Temporal lobe epilepsy (TLE) can develop from alterations in hippocampal structure and circuit characteristics, and can be modeled in mice by administration of kainic acid (KA). We developed a multi-omics experimental setup and analyzed hippocampal (specifically dentate gyrus) tissue samples using proteomics, transcriptomics and microRNA profiling techniques, detecting the expression of 2327 proteins, 13401 mRNAs and 311 microRNAs. Our data may help to further identify and characterize molecular mechanisms involved in the alterations induced shortly after KA-SE in the mouse hippocampus. We present a full description of how these data were obtained and make them available for further analysis and validation in a recent Open Access Publication in Nature's Scientific Data, which can be found here:

Inflammation is a complex protective biological reaction aimed at eliminating the initial cause of tissue injury, clear out damaged and necrotic cells and initiate tissue repair. The inflammatory reaction takes place in all tissues, including the brain, and involves a multitude of different local and systemic mediators at different stages, such as histamine and glucocorticoid hormones. However, how these mediators may work together is still under debate. Our recent work provides an extensive characterisation of molecular mechanisms underlying the interaction between (anti)histamine(s) and glucocorticoids and contributes to understanding dosage optimisation and well-described side effects associated with glucocorticoid administration for the treatment of inflammatory diseases. The open access article can be found here:

Adult neurogenesis continuously contributes new neurons to hippocampal circuits and the programmed death of a subset of immature cells provides a primary mechanism controlling this contribution. We have recently described for the first time that the combinatorial action of two microRNAs, miR-124 and miR-137 fine-tunes the expression of the proapoptotic protein BCL2L13, which controls casp3 activity and thereby favors non-apoptotic caspase-3 functions in NSPC exposed to seizures.

This new mechanism may contribute to the early neurogenic response to epileptic seizures in the dentate gyrus. The open acess article can be found here:

My presentation to the Adult Neurogenesis Meeting in Dresden, in which I reported our findings on the epigenetic regulation of neural stem cells in the adult hippocampus has been highlighted in the scientific news website "The Node" mantained by The Company of Biologists:

Lynnet Frijling, Master student at the Fitzsimon's Lab, won one of the Best Poster prizes at the last Dutch Neuroscience meeting 2015 for her work entitled "Modulation of adult hippocampal neurogenesis after intrahippocampal Kainic Acid- induced seizures using microRNAs". Congratulations Lynnet!!

The International Foundation for Alzheimer's Research (Internationale Stichting Alzheimer Onderzoek (ISAO)) has recently funded 10 new research lines to a total of 1.100.000 euro. I feel very proud that my lab is one of the awardees. The project is aimed to investigate the epigenetic programming of hippocampal neurogenesis by stress in sporadic Alzheimer’s disease models.

Most current animal models of Alzheimer’s disease (AD) are based on the expression of mutated genes associated with the familiar form of AD. These models have played a major role in identifying pathological mechanisms linked to and in evaluating novel therapies. However, familial AD affects only a minority of AD patients. Moreover, in these models pathology starts early in life and is driven fundamentally by the expression of the mutated gene, making them especially unsuitable for the study of the effect of environmental factors, such as stress, on AD progression.

This project covers experimentally a part of the concepts on epigenetic regulation of neural stem cells we have put forward in a recent article published in a highly accessed article in Molecular Neurodegeneration, a Journal dedicated to all aspects of neurodegeneration research at the molecular and cellular levels. This article is open access and can be found at:

In 2014, Erik Betzig, Stefan W. Hell and W. E. Moerner received the the Nobel Prize in Chemistry 2014 for the development of super-resolution fluorescence microscopy. This is a group of techniques developed to overcome the long-standing limitation imposed by light's diffraction limit. Before this development diffraction limit prevented light microscopy from being used to unveil details of cellular structure and function. In Neuroscience, the imaging of the synapse physical location represented by dendritic spines is affected by this limitation. We have recently described a method to apply Structured Illumination Microscopy (SIM), a super-resolution technique, to the detailed imaging of dendritic spined. The article, published in the video journal The Journal of Visualized Experiment (JoVE) is available here:

On May 22, 2014, I received the Top Paper Prize 2014, awarded by the Dutch Neurofederation. The award ceremony took place during the 2014 EndoNeuroPsycho Meeting in Lunteren. After accepting the prize in the name of all the paper's authors, I gave a plenary lecture discussing the main findings of the paper.

Recently, I gave some invited oral presentations in international scientific
meetings:

The 2012 Meeting of the SFN:

http://www.abstractsonline.com/Plan/SSResults.aspx

The 2013 Eurogenesis Meeting in Bordeaux

http://www.eurogenesis.com/

And the 2013 SENS meeting in Oviedo

http://www.senc2013.com/ponentes.html

My presentation at the last Abcam’s Meeting "Regulation of Adult
Neurogenesis: From Epigenetics to Behavior", held on July 12-13th 2012 in
Barcelona as satellite event to the 2012's FENS meeting, has been highlighted
together with those From G. Kempermann, F. Gage and A. Fischer, in Epigenie, a
blog dedicated to epigenetics news:

We have recently published a new article in Molecular Psychiatry where we
describe the role of the Glucocorticoid Receptor in the regulation of adult
hippocampal neurogenesis and fear-motivated behavior:

Master internships available

We are looking for a very motivated and capable Master student (second internship preferably) to study the regulation of adult hippocampal neurogenesis by microRNAs, following our recent publication:

http://www.nature.com/articles/srep12448

Please contact me if you are interested

Previously on...

We were amongst the six finalist of the 2012's version of the Amsterdam Science Innovation Award (AMSIA). The AMSIA is a competition between researchers and students from the University of Amsterdam (UvA), the Academic Medical Centre (AMC), the Amsterdam Technical Highschool (HvA) and other research Institutes with innovative, originale and applicable ideas. We were honored to receive the Public's Award for the project "Modular Proteins as innovative non-viral vectors for gene therapy". This project is a collaboration between the Fitzsimons' Lab and The Institute of Biotechnology and Biomedicine, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, University of Barcelona, Spain.

Research Interests

Neural stem cells, hormones and microRNAs
Experiments at the laboratory are aimed at understanding the
role of microRNAs and hormones in the generation of new neurons
in the hippocampus. In doing so,we focus our work inutilizing
RNA interference (RNAi) as a tool to study and treating
neurologic diseases, such as epilepsy, depression and others,
that may be related to chronic alterations in hippocampal
neurogenesis.
We use a wide range of RNAi effectors from synthetic siRNAs to
short hairpin RNAs and artificial microRNAs. In combination
with viruses engineered and optimized to deliver RNAi effectors
to stem cells and newborn neurons in the hippocampus in vivo,
our experimental approach provides and excellent opportunity to
contribute substantially to a currently booming scientific
field.

Within this line of research, we are particularly interested in studying the interplay between microRNAs and hormone receptors in the regulation of neural stem cells in vitro and in vivo.

A central interest of the lab is the role of hormone receptors and microRNAs in the regulation of synaptic connectivity at the level of dendritic spines. With this aim we use state-of-the-art microscopy techniques.

Nuclear receptor and G-protein coupled receptor signaling

A second part of the group's research focuses on understanding the molecular mechanisms involved in crosstalk between GPCRs and between GPCRs and nuclear receptors for hormones

Fitzsimons, C. P. (invited speaker) (5-11-2015). Role of microRNAs in Aberrant Hippocampal Neurogenesis Associated with Epilepsy., Invited lecture organized by the PhD Program of the Italian Institute of Technology, Genoa, Italy.